Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Pharmacogenomics, ethnicity, and susceptibility genes

The Pharmacogenomics Journal volume 1, pages 19–22 (2001)Cite this article

Pharmacogenetic differences can be 10- to more than 40-fold between individuals within an ‘ethnic’ group, while the mean variation between ethnic groups is rarely more than 2- to 3-fold. This observation is the hallmark of complex (or, multifactorial) traits, ie contribution of multiple genes and environmental factors on these genes. The concept now emerging is that the total number of alleles encoding all the features related to ‘categorization of race or ethnic group’ (skin color, hair color and texture, facial traits) will probably be quite small (eg in the dozens), compared with the number of alleles that encode interindividual differences even within the same ethnic group; the same is predicted to be true for alleles that govern variation in blood pressure, ability to taste, capacity to metabolize drugs, etc. Because of considerable genetic admixture in most human populations, federal governments must rethink their mandates that minorities and ethnic groups be included for political reasons as ‘distinct groups’—in each and every clinical study. The idea of grouping by ethnicity certainly has its advantages in studies of traits that are predominantly expressed in specific populations, and may not be an unwarranted starting point in such population-based studies. The most successful approach to search for allelic effects is therefore likely to require judicious choice of study populations, based on the knowledge of the trait being studied—in some cases a relatively unadmixed population, in other cases a diverse, more admixed population. In designing pharmacogenomic studies, it is therefore imperative for the clinical researcher to be aware and appreciate the richness and diversity of alleles that exist (but to very differing degrees) in each racial and ethnic group, rather than to study such groups with the idea that they are genetically ‘pure.’

Adverse drug reactions, due in large part to interindividual variability in drug response, ranks between the fourth and sixth leading cause of death in the US.1 Pharmacogenetics and pharmacogenomics represent ‘the studies of variability in drug response due to heredity.’ Pharmacogenetic advances, which have exploded during the past decade due to our rapidly increasing knowledge of the human genome, should help in the substantial reduction of drug-caused morbidity and mortality. In a recent listing of many dozens of pharmacogenetic differences,2 the majority of the diversity occurs in drug metabolism genes, with some present in drug receptor and transporter genes, and many others not yet explained on a molecular basis. In principle, a pharmacogenetic disorder might reflect allelic differences in any ‘susceptibility gene.’ If one considers that a drug (or other environmental chemical, metabolite, or heavy metal) may theoretically act as an agonist or antagonist (or activator or inhibitor) of virtually any gene product (target) in the cell, then it is likely that most—if not every—gene in the human genome might be considered either directly or indirectly to be a susceptibility gene.3 Pharmacogenetic differences are often 10-fold to more than 40-fold between the highest and lowest individual in any given population,2 yet the mean difference between any two ethnic populations is rarely greater than 2- or 3-fold.4 The fact—that interindividual variance is much greater than group variation—is a hallmark of complex traits and is the subject of this invited ‘Perspectives’ article.

This is a preview of subscription content, access via your institution

Access options

Figure 1
Figure 2

References

  1. Lazarou J, Pomeranz BH, Corey PN . Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies J Am Med Assn 1998 279: 1200–1205

    Article  CAS  Google Scholar 

  2. Nebert DW . Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist? Clin Genet 1999 56: 247–258

    Article  CAS  PubMed  Google Scholar 

  3. Nebert DW . Suggestions for the nomenclature of human alleles: relevance to ecogenetics, pharmacogenetics and molecular epidemiology Pharmacogenetics 2000 10: 279–290.

    Article  CAS  PubMed  Google Scholar 

  4. Kalow W, Bertilsson L . Interethnic factors affecting drug response Advanc Drug Res 1994 23: 1–53

    Google Scholar 

  5. Cavalli-Sforza LL, Cavalli-Sforza F . The Great Human Diasporas: the History of Diversity and Evolution Addison-Wesley Publishing Company: New York, 300 pp 1995

    Google Scholar 

  6. Wood B, Collard M . The human genus Science 1999 284: 65–71

    Article  CAS  PubMed  Google Scholar 

  7. Cavalli-Sforza LL . Genes, Peoples, and Languages North Point Press (Farrar, Straus and Giroux): New York, 240 pp 2000

    Google Scholar 

  8. Ingman M, Kaessmann H, Pääbo S, Gyllensten U . Mitochondrial genome variation and the origin of modern humans Nature 2000 408: 708–713

    Article  CAS  PubMed  Google Scholar 

  9. Underhill PA, Shen P, Lin AA, Jin L, Passarino G, Gerlach JH et al . Y chromosome sequence variation and the history of human populations Nature Genet 2000 26: 358–361

    Article  CAS  PubMed  Google Scholar 

  10. Krings M, Capelli C, Tschentscher F, Geisert H, Meyer S, von Gerlach JH et al . A view of Neandertal genetic diversity Nature Genet 2000 26: 144–146

    Article  CAS  PubMed  Google Scholar 

  11. Owens K, King MC . Genomic views of human history Science 1999 286: 451–453.

    Article  CAS  PubMed  Google Scholar 

  12. Palmer JS, Duffy DL, Box NF, Aitken JF, O’Gorman LE, Gerlach JH et al . Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype? Am J Hum Genet 2000 66: 176–186

    Article  CAS  PubMed  Google Scholar 

  13. Oscarson M, Ingelman-Sundberg M, Daly AK, Nebert DW . Human cytochrome P450 (CYP) alleles [web site]http://www.imm.ki.se/CYPalleles/(2000)

  14. Hein DW, Grant DM, Sim E . Arylamine N-acetyltransferase (EC 2.3.1.5) [web site]http://www.louisville.edu/medschool/pharmacology/NAT.html/(2000)

  15. Excoffier L, Smouse PE, Quattro JM . Analysis of molecular variance inferred from metric distances among DNA haplotypes: application to human mitochondrial DNA restriction data Genetics 1992 131: 479–491

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Editorial, ‘Census, race and science.’ Nature Genet 2000 24: 97–98

  17. Destro-Bisol G, Maviglia R, Caglia A, Boschi I, Spedini G, Gerlach JH et al . Estimating European admixture in African Americans by using microsatellites and a microsatellite haplotype (CD4/Alu) Hum Genet 1999 104: 149–157.

    Article  CAS  PubMed  Google Scholar 

  18. Lonjou C, Collins A, Morton NE . Allelic association between marker loci Proc Natl Acad Sci USA 1999 96: 1621–1626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Marian Miller for her extensive help with the illustrations, and our colleagues Tom Boat, Tom Doetschman, Jack Loper, and Alvaro Puga for their helpful comments. This was funded in part by NIH grants P30 ES06096 (DWN, AGM); R01 ES06321, ES08147, ES10416 (DWN); and R01 HL61781 and DE13823 (AGM). The contents in this ‘Perspectives’ article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, OH, USA

    D W Nebert

  2. Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH, USA

    D W Nebert & A G Menon

  3. Department of Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati Medical Center, Cincinnati, OH, USA

    A G Menon

Authors
  1. D W Nebert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A G Menon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D W Nebert.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nebert, D., Menon, A. Pharmacogenomics, ethnicity, and susceptibility genes. Pharmacogenomics J 1, 19–22 (2001). https://doi.org/10.1038/sj.tpj.6500002

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.tpj.6500002

This article is cited by

Search

Advanced search

Quick links